Heterocyclylalkoxy-, -alkylthio- and -alkylaminobenzazole derivatives as 5-hydroxytryptamine-6 ligands

ABSTRACT

The present invention provides a compound of formula I and the use thereof for the therapeutic treatment of disorders relating to or affected by the 5-HT6 receptor.

This application claims priority from copending application Ser. No.60/285644, filed on Apr. 20, 2001, the entire disclosure of which ishereby incorporated by reference.

BACKGROUND OF THE INVENTION

Various central nervous system disorders such as anxiety, depression,motor disorders, etc., are believed to involve a disturbance of theneurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin islocalized in the central and peripheral nervous systems and is known toaffect many types of conditions including psychiatric disorders, motoractivity, feeding behavior, sexual activity, and neuroendocrineregulation among others. The effects of serotonin are regulated by thevarious 5-HT receptor subtypes. Known 5-HT receptors include the 5-HT1family (e.g. 5-HT1A), the 5-HT2 family (e.g. 5-HT2A), 5-HT3, 5-HT4,5-HT5, 5-HT6 and 5-HT7 subtypes.

The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptorsubtype has been cloned, and the extensive distribution of its mRNA hasbeen reported. Highest levels of 5-HT6 receptor mRNA have been observedin the olfactory tubercle, the striatum, nucleus accumbens, dentategyrus and CA1, CA2 and CA3 regions of the hippocampus. Lower levels of5-HT6 receptor mRNA were seen in the granular layer of the cerebellum,several diencephalic nuclei, amygdala and in the cortex. Northern blotshave revealed that 5-HT6 receptor mRNA appears to be exclusively presentin the brain, with little evidence for its presence in peripheraltissues. The high affinity of a number of antipsychotic agents for the5-HT6 receptor, in addition to its mRNA localization in striatum,olfactory tubercle and nucleus accumbens suggests that some of theclinical actions of these compounds may be mediated through thisreceptor. Therefore, 5-HT6 receptor ligands are believed to be ofpotential use in the treatment of certain CNS disorders such as anxiety,depression, epilepsy, obsessive compulsive disorders, attention deficitdisorder, migraine, cognitive memory enhancement (e.g. for the treatmentof Alzheimer's disease), sleep disorders, feeding disorders (e.g.anorexia and bulimia), panic attacks, withdrawal from drug abuse (e.g.cocaine, ethanol, nicotine and benzodiazepines), schizophrenia, or thelike; or in the treatment of certain gastrointestinal disorders such asirritable bowel syndrome.

Therefore, it is an object of this invention to provide compounds whichare useful as therapeutic agents in the treatment of a variety ofcentral nervous system disorders related to or affected by the 5-HT6receptor.

It is another object of this invention to provide therapeutic methodsand pharmaceutical compositions useful for the treatment of centralnervous system disorders related to or affected by the 5-HT6 receptor.

It is a feature of this invention that the compounds provided may alsobe used to further study and elucidate the 5-HT6 receptor.

These and other objects and features of the invention will become moreapparent by the detailed description set forth hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I

wherein

-   -   W is SO₂, CO, CONH, CSNH or (CH₂)_(x);    -   X is O, SO_(y) or NR₁₃;    -   Y is CR₁₄ or N;    -   Z is CR₁₅ or N with the proviso that when Y is N then Z must be        CR₁₅;    -   m and x are each independently 0 or an integer of 1, 2 or 3;    -   n and p are each independently an integer of 1, 2 or 3;    -   R₁ is halogen, CN, OR₁₆, CO₂R₁₇, CONR₁₈R₁₉, CNR₂₀NR₂₁R₂₂,        SO₂NR₂₃R₂₄, SO_(w)R₂₅, or a C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, phenyl or        heteroaryl group each optionally substituted;    -   R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are each independently H        or an optionally substituted C₁-C₆alkyl group;    -   R₄ is H, CNR₂₆NR₂₇R₂₈ or a C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or        heteroaryl group each optionally substituted;    -   R₁₂ is an optionally substituted C₁-C₆alkyl, aryl or heteroaryl        group;    -   y and w are each 0 or an integer of 1 or 2;    -   R₁₃ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each        optionally substituted;    -   R₁₄ and R₁₅ are each independently H, halogen or a C₁-C₆alkyl,        aryl, heteroaryl or C₁-C₆alkoxy group each optionally        substituted;    -   R₁₆ is H, COR₂₉ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        aryl or heteroaryl group each optionally substituted;    -   R₁₇ and R₂₉ are each independently H or a C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl,        aryl or heteroaryl group each optionally substituted;    -   R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₆, R₂₇ and R₂₈ are each independently        H or an optionally substituted C₁-C₆alkyl group;    -   R₂₃ and R₂₄ are each independently H or a C₁-C₆alkyl, aryl or        heteroaryl group each optionally substituted; and    -   R₂₅ is an optionally substituted C₁-C₆alkyl, aryl, or heteroaryl        group; or        the stereoisomers thereof or the pharmaceutically acceptable        salts thereof.

The present invention also provides methods and compositions useful forthe therapeutic treatment of central nervous system disorders related toor affected by the 5-HT6 receptor.

The present invention further provides a method for the preparation ofcompounds of formula I and a compound useful therefor.

DETAILED DESCRIPTION OF THE INVENTION

The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recentreceptors to be identified by molecular cloning. Its ability to bind awide range of therapeutic compounds used in psychiatry, coupled with itsintriguing distribution in the brain has stimulated significant interestin new compounds which are capable of interacting with or affecting saidreceptor. At present, there are no known fully selective agonists.Significant efforts are being made to understand the possible role ofthe 5-HT6 receptor in psychiatry, cognitive dysfunction, motor functionand control, memory, mood and the like. To that end, compounds whichdemonstrate a binding affinity for the 5-HT6 receptor are earnestlysought both as an aid in the study of the 5-HT6 receptor and aspotential therapeutic agents in the treatment of central nervous systemdisorders.

Surprisingly, it has now been found that heterocyclylalkoxy-, -thioxy-or -aminobenzazole derivatives of formula I demonstrate 5-HT6 affinity.Advantageously, said benzazole derivatives may be used as effectivetherapeutic agents for the treatment of central nervous system (CNS)disorders associated with or affected by the 5-HT6 receptor.Accordingly, the present invention provides heterocyclylalkoxy-,-alkylthio- or -alkylaminobenzazole derivatives of formula I

wherein

-   -   W is SO₂, CO, CONH, CSNH or (CH₂)_(x);    -   X is O, SO_(y) or NR₁₃;    -   Y is CR₁₄ or N;    -   Z is CR₁₅ or N with the proviso that when Y is N then Z must be        CR₁₅;    -   m and x are each independently 0 or an integer of 1, 2 or 3;    -   n and p are each independently an integer of 1, 2 or 3;    -   R₁ is halogen, CN, OR₁₆, CO₂R₁₇, CONR₁₈R₁₉, CNR₂₀NR₂₁R₂₂,        SO₂NR₂₃R₂₄, SO_(w)R₂₅, or a C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, phenyl or        heteroaryl group each optionally substituted;    -   R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are each independently H        or an optionally substituted C₁-C₆alkyl group;    -   R₄ is H, CNR₂₆NR₂₇R₂₈, or a C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or        heteroaryl group each optionally substituted;    -   R₁₂ is an optionally substituted C₁-C₆alkyl, aryl or heteroaryl        group;    -   y and w are each 0 or an integer of 1 or 2;    -   R₁₃ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each        optionally substituted;    -   R₁₄ and R₁₅ are each independently H, halogen or a C₁-C₆alkyl,        aryl, heteroaryl or C₁-C₆alkoxy group each optionally        substituted;    -   R₁₆ is H, COR₂₉ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        aryl or heteroaryl group each optionally substituted;    -   R₁₇ and R₂₉ are each independently H or a C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl,        aryl or heteroaryl group each optionally substituted;    -   R₁₈, R₁₉, R₂₀, R₂₁, R₂₆, R₂₇ and R₂₈ are each independently H or        an optionally substituted C₁-C₆alkyl group;    -   R₂₃ and R₂₄ are each independently H or a C₁-C₆alkyl, aryl or        heteroaryl group each optionally substituted; and    -   R₂₅ is an optionally substituted C₁-C₆alkyl, aryl, or heteroaryl        group; or        the stereoisomers thereof or the pharmaceutically acceptable        salts thereof.

As used in the specification and claims, the term halogen designates Br,Cl, I or F and the term cycloheteroalkyl designates a C₅-C₇cycloalkylring system containing 1 or 2 heteroatoms, which may be the same ordifferent, selected from N, O or S and optionally containing one doublebond. Exemplary of the cycloheteroalkyl ring systems included in theterm as designated herein are the following rings wherein X₁ is NR, O orS.

Similarly, as used in the specification and claims, the term heteroaryldesignates a 5- to 10-membered aromatic ring system containing 1 or 2heteroatoms, which may be the same or different, selected from N, O orS. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl,thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl,indolinyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like. Theterm haloalkyl as used herein designates a C_(n)H_(2n+1) group havingfrom one to 2n+1 halogen atoms which may be the same or different andthe term haloalkoxy as used herein designates an OC_(n)H_(2n+1) grouphaving from one to 2n+1 halogen atoms which may be the same ordifferent.

In the specification and claims, when the terms C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, phenyl orheteroaryl are designated as being optionally substituted, thesubstituent groups which are optionally present may be one or more ofthose customarily employed in the development of pharmaceuticalcompounds or the modification of such compounds to influence theirstructure/activity, persistence, absorption, stability or otherbeneficial property. Specific examples of such substituents includehalogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl,haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl,alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl,alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl,benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atomsor lower alkyl groups. Typically, 0-3 substituents may be present. Whenany of the foregoing substituents represents or contains an alkylsubstituent group, this may be linear or branched and may contain up to12, preferably up to 6, more preferably up to 4 carbon atoms.

Pharmaceutically acceptable salts may be any acid addition salt formedby a compound of formula I and a pharmaceutically acceptable acid suchas phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic,malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic,p-toluene sulfonic, methane sulfonic acid or the like.

Compounds of the invention may exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. One skilled in the art will appreciate that onestereoisomer may be more active or may exhibit beneficial effects whenenriched relative to the other stereoisomer(s) or when separated fromthe other stereoisomer(s). Additionally, the skilled artisan knows howto separate, enrich or selectively prepare said stereoisomers.Accordingly, the present invention comprises compounds of Formula I, thestereoisomers thereof and the pharmaceutically acceptable salts thereof.The compounds of the invention may be present as a mixture ofstereoisomers, individual stereoisomers, or as an opticaly active form.

Preferred compounds of the invention are those compounds of formula Iwherein W is SO₂ or CO. Also preferred are those compounds of formula Iwherein X is O. Another group of preferred compounds of the inventionare those compounds of formula I wherein Y is CR₁₄.

Further preferred compounds of the invention are those compounds offormula I wherein R₁₂ is an aryl or heteroaryl group each optionallysubstituted; and n is 1.

More preferred compounds of the invention are those compounds of formulaI wherein W is SO₂; X is O; and n is 1. Another group of more preferredcompounds of the invention are those compounds of formula I wherein W isSO₂; X is O; Y is CR₁₄; n is 1; and p is 1.

Among the preferred compounds of the invention are:

-   -   1-(phenylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;    -   1-[(5-chlorothien-2-yl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;    -   1-[(2-fluorophenyl)sulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;    -   1-[(3-fluorophenyl)sulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;    -   1-[(4-fluorophenyl)sulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;    -   1-[(3,4-dimethoxyphenyl)sulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;    -   4-({4-[2S)-pyrrolidin-2-ylmethoxy]-1H-indole-1-yl}sulfonyl)aniline;    -   1-(phenylsulfonyl)-4-[(2R)-pyrrolidin-2-ylmethoxy]-1H-indole;    -   1-(phenylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    -   8-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)quinoline;    -   1-[(2-chlorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    -   1-[(2-fluorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    -   1-[(5-chlorothien-2-yl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;    -   4-({4-[(2S)-pyrrolidin-2-ylmethoxy}-1H-indazol-1-yl}sulfonyl)aniline;    -   2-chloro-4-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)aniline;    -   1-(phenylsulfonyl)-4-(piperidin-2-ylmethoxy)-1H-indole;    -   4-{[4-(piperidin-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;    -   1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;    -   1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;    -   1-[(3-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;    -   1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;    -   1-[(2-chlorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;    -   1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;    -   4-(azepan-2-ylmethoxy)-1-(phenylsulfonyl)-1H-indole;    -   4-{[4-(azepan-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;    -   4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indole;    -   4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indole;    -   4-(azepan-2-ylmethoxy)-1-[(3-fluorophenyl)sulfonyl]-1H-indole;    -   4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indazole;    -   4-(azepan-2-ylmethoxy)-1-[(2-chlorophenyl)sulfonyl]-1H-indazole;    -   4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indazole;    -   1-(phenylsulfonyl)-5-(pyrrolidin-2-ylmethoxy)-1H-indole;    -   1-(phenylsulfonyl)-6-(pyrrolidin-2-ylmethoxy)-1H-indole;    -   1-(phenylsulfonyl)-5-(pyrrolidin-2-ylmethoxy)-1H-indazole;    -   1-(phenylsulfonyl)-6-(pyrrolidin-2-ylmethoxy)-1H-indazole; or        the stereoisomers thereof or the pharmaceutically acceptable        salts thereof.

Compounds of the invention may be prepared using conventional syntheticmethods and, if required, standard separation and isolation techniques.For example, compounds of formula I wherein W is SO₂; X is O; Y is CR₁₃;Z is CR₁₄; and R₄ and R₁₁ are H (Ia) may be prepared by reacting anhydroxyindole of formula II with an N-protected-2-methoxyheterocycle offormula III in the presence of triphenylphosphine and diethylazodicarboxylate to give the corresponding indol-4-yloxyalkylheterocycleof formula IV. Subsequent sulfonylation and deprotection of the formulaIV compound gives the desired formula Ia product. The reaction sequenceis illustrated in flow diagram I wherein P represents a protectinggroup.

Commonly used protecting groups include t-butyl-carboxylate, benzyl,acetyl, benzyloxycarbonyl, or any conventional group known to protect abasic nitrogen in standard synthetic procedures.

Compounds of formula I wherein W is SO₂; X is O; Y is CH; Z is N and R₄and R₁₁ are H (Ib) may be prepared by reacting a nitromethylphenol offormula V with an N-protected-2-alkoxyheterocyclic compound of formulaIII in the presence of triphenylphosphine and diethyl azodicarboxylateto give the corresponding heterocyclylalkoxybenzene of formula VI,reducing the nitro group of the formula VI compound, for example viacatalytic hydrogenation, to give the amine of formula VII and reactingthe formula VII amine with isoamylnitrite in the presence of potassiumacetate and acetic anhydride to give the heterocyclyalkoxyindazole offormula VIII. Sulfonylation and deprotection of said formula VIIIcompound gives the desired compound of formula Ib wherein R₄ is H.Subsequent reaction of the formula Ib compound with a suitablealkylating reagent such as an alkyl or aralkyl halide, R₄-Hal, givesthose compounds of formula Ib′ wherein R₄ is other than H. The reactionsequence is shown in flow diagram II wherein P is a protecting group andHal is Cl, Br or I.

Compounds of formula I wherein W is SO₂; X is NH; Y is CH; Z is N; andR₄ and R₁₁ are H (Ic) may be prepared by the reductive amination of anN-protected carbonylalkylheterocyclic compound of formula X with anitromethylaniline compound of formula IX to give the compound offormula XI, reducing the nitro group to give the amine of formula XIIand reacting the formula XII amine with isoamylnitrite in the presenceof potassium acetate and acetic anhydride to give theheterocyclylalkylamino-indazole of formula XIII. Subsequentsulfonylation and deprotection as described hereinabove give the desiredcompound of formula Ic. The reaction sequence is shown in flow diagramIII.

Similarly, compounds of formula I wherein W is SO₂; X is NH; Y is CR₁₃;Z is CR₁₄; and R₄ and R₁₁ are H (Id) may be prepared by the reductiveamination of the formula X carboxyaldehyde with an aminoindole offormula XIV to give the compound of formula XV. Subsequent sulfonylationand deprotection gives the desired product of formula Id. The reactionsequence is shown in flow diagram IV.

Compounds of formula I wherein X is S and W is SO₂ may be prepared byemploying the appropriate indolylthiol or thiophenol and utilizing thereactions shown in flow diagrams I and II, respectively.

Compounds of formula I wherein W is CO may be prepared by reacting thebenzazole precursor, for example a compound of formula IV, VIII, XIII orXV with the appropriate isocyanate, carbonyl halide or carbamoyl halidein the presence of a base. Similarly, compounds of formula I wherein Wis (CH₂)_(x) and x is an integer of 1, 2 or 3 may be prepared byreacting the appropriately substituted alkylhalide with a compound offormula IV, VIII, XIII or XV in the presence of a base. Compounds offormula I wherein W is (CH₂)_(x) and x is 0 may be prepared via apalladium-catalyzed N-arylation such as that descrited by D. W. Old etal, Organic Letters, 2000 (2), pp 1403-1406. Using these and otherconventional methods, compounds of formula I may be prepared fromreadily available starting materials.

Advantageously, the present invention provides a compound of formula XVI

wherein X, Y, Z, m, n, p, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ andR₁₁ are as defined for formula I. Compounds of formula XVI are useful inthe preparation of the therapeutic agents of formula I describedhereinabove. Accordingly, the present invention also provides a methodfor the preparation of a compound of formula I wherein W is SO₂ (Ie)which comprises reacting a formula XVI compound with a sulfonylchloride, R₁₂SO₂Cl, wherein R₁₂ is as defined for formula I in thepresence of a base optionally in the presence of a solvent. The reactionis shown in flow diagram V.

Bases suitable for use in the method of invention are strong bases suchas NaH, KOt-Bu, or any conventional base capable of removing a protonfrom a basic indole or benzazole nitrogen-atom.

Advantageously, the inventive compound of formula I may be utilized inthe treatment of central nervous system disorders relating to oraffected by the 5-HT6 receptor such as motor, mood, psychiatric,cognitive, neurodegenerative, or the like disorders, for example,Alzheimer's disease, Parkinson's disease, attention deficit disorder,anxiety, epilepsy, depression, obsessive compulsive disorder, migraine,sleep disorders, feeding disorders (such as anorexia or bulimia),schizophrenia, memory loss, disorders associated with withdrawl fromdrug abuse, or the like or certain gastrointestinal disorders such asirritable bowel syndrome. Accordingly, the present invention provides amethod for the treatment of a disorder of the central nervous system(CNS) related to or affected by the 5-HT6 receptor in a patient in needthereof which comprises providing said patient a therapeuticallyeffective amount of a compound of formula I as described hereinabove.The compounds may be provided by oral or parenteral administration or inany common manner known to be an effective administration of atherapeutic agent to a patient in need thereof.

The therapeutically effective amount provided in the treatment of aspecific CNS disorder may vary according to the specific condition(s)being treated, the size, age and response pattern of the patient, theseverity of the disorder, the judgment of the attending physician andthe like. In general, effective amounts for daily oral administrationmay be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg andeffective amounts for parenteral administration may be about 0.1 to 100mg/kg, preferably about 0.5 to 50 mg/kg.

In actual practice, the compounds of the invention are provided byadministering the compound or a precursor thereof in a solid or liquidform, either neat or in combination with one or more conventionalpharmaceutical carriers or excipients. Accordingly, the presentinvention provides a pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound of formula I as described hereinabove.

Solid carriers suitable for use in the composition of the inventioninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

Compositions of the invention which are sterile solutions or suspensionsare suitable for intramuscular, intraperitoneal or subcutaneousinjection. Sterile solutions may also be administered intravenously.Inventive compositions suitable for oral administration may be in eitherliquid or solid composition form.

For a more clear understanding, and in order to illustrate the inventionmore clearly, specific examples thereof are set forth hereinbelow. Thefollowing examples are merely illustrative and are not to be understoodas limiting the scope and underlying principles of the invention in anyway.

Unless otherwise stated, all parts are parts by weight. The term NMRdesignates nuclear magnetic resonance. The terms THF and EtOAc designatetetrahydrofuran and ethyl acetate, respectively.

EXAMPLE 1 Preparation of t-Butyl(2S)-2-[(1H-indol-4-yloxy)methyl]-1-pyrrolidinecarboxylate

A solution of 4-hydroxyindole (1.33 g, 10.0 mmol),(S)-(−)-1-t-butoxycarbonyl)-2-pyrrolidine methanol (4.02 g, 20.0 mmol)and triphenylphosphine (5.3 g, 20.0 mmol) in THF is treated with diethylazodicarboxylate (3.2 mL, 20.0 mmol) under nitrogen at room temperature,stirred for 2 h at room temperature and concentrated in vacuo. Theresultant residue is purified by flash chromatography (silica gel,EtOAc/hexane: 20/80) to give the title compound as a white solid, 1.5 g,mp 40-41° C., identified by NMR and mass spectral analyses.

EXAMPLE 2 Preparation of t-Butyl(2S)-2-({[1-(Phenylsulfonyl)-1H-indol-4-yl]oxy}methyl)-1-pyrrolidinecarboxylate

A stirred solution of t-butyl(2S)-2-[(1H-indol-4-yloxy)methyl]-1-pyrrolidinecarboxylate (1.23 g, 3.89mmol) in THF is treated with sodium hydride (0.17 g, 60% in mineral oil,4.28 mmol) under nitrogen at room temperature, stirred for 30 minutes,treated with benzenesulfonyl chloride (0.55 mL, 4.28 mmol), stirred atroom temperature for 22 h, quenched with ice-water and diluted withEtOAc. The organic phase is separated, washed sequentially with waterand brine, dried over MgSO₄ and concentrated in vacuo. The resultantresidue is purified by flash chromatography (siliga gel, EtOAc/hexanes,2/8) to afford the title compound as an off-white foam, 1.21 g, mp48-50° C., identified by NMR and mass spectral analyses.

EXAMPLE 3 Preparation of1-(Phenylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indolehydrochloride

A solution of t-butyl(2S)-2-({[1-phenylsulfonyl)-1H-indol-4-yl]oxy}methyl)-1-pyrrolidinecarboxylate(1.06 g, 2.32 mmol) in methanol and HCl (11.6 mL 1M in ether) is heatedat 60° C. under nitrogen for 2 h, cooled to room temperature andconcentrated in vacuo. The resultant residue is treated with EtOAc andfiltered. The filtercake is dried in vacuo to give the title compound asan off-white solid, 0.89 g, mp 194-196° C., identified by NMR and massspectral analyses.

EXAMPLES 4-9 Preparation of1-(Arylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole Hydrochloride

Using essentially the same procedure described in Examples 2 and 3hereinabove and employing potassium t-butoxide and the appropriatearylsulfonyl chloride, the compounds shown in Table I are obtained andidentified by NMR and mass spectral analyses. TABLE I

Example mp No. R₁₂ X ° C. 4 5-chlorothien-2-yl 1 204-206 52-fluorophenyl 1 153-155 6 3-fluorophenyl 1 160-162 7 4-fluorophenyl 1258 (dec) 8 3,4-dimethoxyphenyl 1 115 (dec) 9 4-aminophenyl 2 150 (dec)

EXAMPLE 10 Preparation of t-Butyl(2R)-2-[(1H-indol-4-yloxy)methyl]-pyrrolidine-1-carboxylate

A stirred solution of 4-hydroxyindole (1.33 g, 10.0 mmol),(R)-(+)-1-(t-butoxycarbonyl)-2-pyrrolidinemethanol (4.02 g, 20.0 mmol)and triphenylphosphine (5.3 g, 20.0 mmol) in THF is treated with diethylazodicarboxylate (3.2 mL, 20 mmol), stirred for 3 h at room temperatureand concentrated in vacuo. The resultant residue is treated with EtOAcand filtered through a pad of silica gel. The filtrate is concentratedto give a residue which is purified by chromatography (silica gel,EtOAc:hexanes, 15:80) to afford the title compound as a white solid,1.08 g, mp 146-147° C.; identified by NMR and mass spectral analyses.

EXAMPLE 11 Preparation of1-(Phenylsulfonyl)-4-[(2R)-]pyrrolidin-2-ylmethoxy]-1H-indolehydrochloride

A solution of t-butyl(2R)-2-[(1H-indol-4-yloxy)methyl]pyrrolidine-1-carboxylate (0.316 g, 1.0mmol) in THF is treated with potassium t-butoxide (1.5 mL, 1.5 mmol, 1Min THF) at room temperature, stirred for 3 min, treated withbenzenesulfonyl chloride (0.264 g, 1.5 mmol), stirred for 6 h undernitrogen at room temperature, quenched with 1N aqueous HCl and water anddiluted with EtOAc. The organic phase is separated, washed sequentiallywith water and brine, dried over MgSO₄ and concentrated in vacuo. Theresultant residue is treated with HCl (1.5 mL, 1N in Et₂O), heated atreflux temperature for 3 h, cooled to room temperature and filtered. Thefiltercake is air-dried to afford the title compound as an off-whitesolid, 0.24 g, mp 204-206° C., identified by NMR and mass spectralanalyses.

EXAMPLE 12 Preparation of t-Butyl(2S)-2-[(2-methyl-3-nitrophenoxy)methyl]pyrrolidine-1-carboxylate

A stirred solution of 2-methyl-3-nitrophenol (3.80 g, 24.84 mmol),(S)-(−)-1-tert-butoxycarbonyl)-2-pyrrolidinemethanol (5.0 g, 24.8 mmol)and triphenylphosphine (6.5 g, 24.8 mmol) in THF is treated withdiethylazodicarboxylate (4.3 g, 24.8 mmol), stirred for 3 h at roomtemperature and concentrated in vacuo. The resultant residue is mixedwith ether, stored at 0° C. overnight and filtered. The filtrate isconcentrated in vacuo to give a residue which is purified bychromatography (silica gel, EtOAc:hexanes, 20:80) to afford the titlecompound as a light yellow semisolid, 7.73 g, (91% yield), identified byNMR and mass spectral analyses.

EXAMPLE 13 Preparation of t-Butyl(2S)-2-[(3-amino-2-methylphenoxy)methyl]pyrrolidine-1-carboxylate

A solution of t-butyl(2S)-2-[(2-methyl-3-nitrophenoxy)methyl]pyrrolidine-1-carboxylate (7.63g, 21.9 mmol) and 10% Pd/C (0.38 g) in ethanol is hydrogenated (50 psi)at room temperature for 4 h and filtered. The filtrate is concentratedin vacuo to afford the title compound as an off-white solid, 6.66 g, mp110° C., identified by NMR and mass spectral analyses.

EXAMPLE 14 Preparation of t-Butyl(2S)-2-[(1H-indazol-4-yloxy)methyl]pyrrolidine-1-carboxylate

A solution of t-butyl (2S)-2-[(3-amino-2-methylphenoxy)methyl]pyrrolidine-1-carboxylate (5.00 g, 16.33 mmol), potassium acetate(1.92 g, 19.6 mmol) and acetic anhydride (4.9 mL, 52.3 mmol) in benzeneis treated dropwise with isoamylnitrite (4.3 mL, 32.7 mmol), heated atreflux temperature overnight, cooled to room temperature and filtered.The filtercake is washed with benzene. The filtrates are combined andconcentrated in vacuo to give a yellow oil residue. The residue ispurified by chromatography (silica gel, EtOAc:hexanes, 15:85). Thepurified oil (5.05 g) is dissolved in ethanol, treated with 40% aqueousNaOH, heated at reflux temperature for 45 min, cooled in an ice-waterbath, neutralized to pH 8 with concentrated HCl and concentrated invacuo to remove the ethanol. The resultant aqueous residue is extractedwith EtOAc. The combined extracts are washed sequentially with water andbrine, dried over MgSO₄ and concentrated in vacuo to give a yellow oil.This oil is purified by chromatography (silica gel, EtOAc:hexanes,30:70) to give the title product as an off-white solid, 3.52 g, mp 125°C., identified by NMR and mass spectral analyses.

EXAMPLE 15 Preparation of1-(Phenylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazoletrifluoroacetic acid salt

A solution of t-butyl(2S)-2-[(1H-indazol-4-yloxy)methyl]pyrrolidine-1-carboxylate (0.317 g,1.0 mmol) in dimethylformamide is treated with sodium hydride (0.08 g,2.0 mmol, 60% in mineral oil) at room temperature, stirred for 10 min,treated with benzenesulfonyl chloride (0.264 g, 1.5 mmol), stirred for18 h under nitrogen at room temperature, quenched with water and dilutedwith ether. The organic phase is separated, washed sequentially withwater and brine, dried over MgSO₄ and concentrated in vacuo to give awhite foam residue. The residue is purified by chromatography (silicagel, EtOAc:hexanes, 15:85) to give a white solid. This solid isdissolved in trifluoroacetic acid at 0° C., stirred at room temperaturefor 90 min and concentrated in vacuo. The resultant residue istriturated under ether to afford the title compound as a white solid,300 mg, mp 218-219° C., identified by NMR and mass spectral analyses.

EXAMPLES 16-21 Preparation of1-Arylsulfonyl-4[(2S)-pyrrolidinylmethoxy]1H-indazole Hydrochloride

Using essentially the same procedure described in Example 15 hereinaboveand employing the appropriate arysulfonyl chloride and anhydrous HCl,the compounds in Table II are obtained and identified by NMR and massspectral analyses. TABLE II

Example mp No. R₁₂ X ° C. 16 8-quinolinyl 0 217-218 17 2-chlorophenyl1 >255 (dec) 18 2-fluorophenyl 1 145-148 19 5-chlorothien-2-yl 1 195 204-aminophenyl 2 150-155 21 4-amino-3-chlorophenyl 2   220 (dec)

EXAMPLE 22 Comparative Evaluation of 5-HT6 Binding Affinity of TestCompounds

The affinity of test compounds for the serotonin 5-HT6 receptor isevaluated in the following manner. Cultured Hela cells expressing humancloned 5-HT6 receptors are harvested and centrifuged at low speed(1,000×g) for 10.0 min to remove the culture media. The harvested cellsare suspended in half volume of fresh physiological phosphate bufferedsaline solution and recentrifuged at the same speed. This operation isrepeated. The collected cells are then homogenized in ten volumes of 50mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate is centrifuged at40,000×g for 30.0 min and the precipitate is collected. The obtainedpellet is resuspended in 10 volumes of Tris.HCl buffer and recentrifugedat the same speed. The final pellet is suspended in a small volume ofTris.HCl buffer and the tissue protein content is determined in aliquotsof 10-25 μl volumes. Bovine Serum Albumin is used as the standard in theprotein determination according to the method described in Lowry et al.,J. Biol. Chem., 193:265 (1951). The volume of the suspended cellmembranes is adjusted to give a tissue protein concentration of 1.0mg/ml of suspension. The prepared membrane suspension (10 timesconcentrated) is aliquoted in 1.0 ml volumes and stored at −70° C. untilused in subsequent binding experiments.

Binding experiments are performed in a 96 well microtiter plate format,in a total volume of 200 μl. To each well is added the followingmixture: 80.0 μl of incubation buffer made in 50 mM Tris.HCl buffer (pH7.4) containing 10.0 mM MgCl₂ and 0.5 mM EDTA and 20 μl of [³H]-LSD(S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. Thedissociation constant, K_(D) of the [³H] LSD at the human serotonin5-HT6 receptor is 2.9 nM, as determined by saturation binding withincreasing concentrations of [3H] LSD. The reaction is initiated by thefinal addition of 100.0 μl of tissue suspension. Nonspecific binding ismeasured in the presence of 10.0 μM methiothepin. The test compounds areadded in 20.0 μl volume.

The reaction is allowed to proceed in the dark for 120 min at roomtemperature, at which time, the bound ligand-receptor complex isfiltered off on a 96 well unifilter with a Packard Filtermate® 196Harvester. The bound complex caught on the filter disk is allowed to airdry and the radioactivity is measured in a Packard TopCount® equippedwith six photomultiplier detectors, after the addition of 40.0 μlMicroscint®-20 scintillant to each shallow well. The unifilter plate isheat-sealed and counted in a PackardTopCount® with a tritium efficiencyof 31.0%.

Specific binding to the 5-HT6 receptor is defined as the totalradioactivity bound less the amount bound in the presence of 10.0 μMunlabeled methiothepin. Binding in the presence of varyingconcentrations of test compound is expressed as a percentage of specificbinding in the absence of test compound. The results are plotted as log% bound versus log concentration of test compound. Nonlinear regressionanalysis of data points with a computer assisted program Prism® yieldedboth the IC₅₀ and the K_(i) values of test compounds with 95% confidencelimits. A linear regression line of data points is plotted, from whichthe IC₅₀ value is determined and the K_(i) value is determined basedupon the following equation:K _(i) =IC ₅₀/(1+L/K _(D))where L is the concentration of the radioactive ligand used and K_(D) isthe dissociation constant of the ligand for the receptor, both expressedin nM.

Using this assay, the following Ki values are determined and compared tothose values obtained by representative compounds known to demonstratebinding to the 5-HT6 receptor. The data are shown in Table III, below.TABLE III 5-HT6 Binding Ki (nM) Test Compound (Ex. No.) 3 6.0 4 7.0 52.0 6 8.0 7 31.0 8 95.0 9 1.0 11 106 15 7.0 16 85.0 17 5.0 18 8.0 19 5.020 9.0 21 16.0 Comparative Examples Clozapine 6.0 Loxapine 41.4Bromocriptine 23 .0 Methiothepin 8.3 Mianserin 44.2 Olanzepine 19.5

As can be seen from the results set forth above, the compounds of thepresent invention have a high degree of affinity for the 5-HT6 receptor.

1. A compound of formula I

wherein W is SO₂, CO, CONH, CSNH or (CH₂)_(x); X is O, SO_(y) or NR₁₃; Yis CR₁₄ or N; Z is CR₁₅ or N with the proviso that when Y is N then Zmust be CR₁₅; m and x are each independently 0 or an integer of 1, 2 or3; n and p are each independently an integer of 1, 2 or 3 with theproviso that when p is an integer of 1 then one of Y and Z must be N; R₁is halogen, CN, OR₁₆, CO₂R₁₇, CONR₁₈R₁₉, CNR₂₀NR₂₁R₂₂, SO₂NR₂₃R₂₄,SO_(w)R₂₅, or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, phenyl or heteroaryl group each optionallysubstituted; R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently H or an optionally substituted C₁-C₆alkyl group; R₄ is H,CNR₂₆NR₂₇R₂₈ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; R₁₂ is an optionally substituted C₁-C₆alkyl,aryl or heteroaryl group; y and w are each 0 or an integer of 1 or 2;R₁₃ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;R₁₄ and R₁₅ are each independently H, halogen or a C₁-C₆alkyl, aryl,heteroaryl or C₁-C₆alkoxy group each optionally substituted; R₁₆ is H,COR₂₉ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, aryl or heteroarylgroup each optionally substituted; R₁₇ and R₂₉ are each independently Hor a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₆, R₂₇ and R₂₈ are each independently H or anoptionally substituted C₁-C₆alkyl group; R₂₃ and R₂₄ are eachindependently H or a C₁-C₆alkyl, aryl or heteroaryl group eachoptionally substituted; and R₂₅ is an optionally substituted C₁-C₆alkyl,aryl, or heteroaryl group; or the stereoisomers thereof or thepharmaceutically acceptable salts thereof.
 2. The compound according toclaim 1 wherein W is SO₂.
 3. The compound according to claim 1 wherein Xis O.
 4. The compound according to claim 1 wherein Y is CR₁₄.
 5. Thecompound according to claim 1 wherein n is
 1. 6. The compound accordingto claim 2 wherein R₁₂ is an aryl or heteroaryl group each optionallysubstituted.
 7. The compound according to claim 6 wherein X is O and nis
 1. 8. The compound according to claim 7 wherein Y is CR₁₄ and p is 1.9. The compound according to claim 7 selected from the group consistingof 1-(phenylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;8-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)quinoline;1-[(2-chlorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;1-[(2-fluorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;1-[(5-chlorothien-2-yl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;4-({4-[(2S)-pyrrolidin-2-ylmethoxy}-1H-indazol-1-yl}sulfonyl)aniline;2-chloro-4-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)aniline;1-(phenylsulfonyl)-4-(piperidin-2-ylmethoxy)-1H-indole;4-{[4-(piperidin-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;1-[(3-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;1-[(2-chlorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;4-(azepan-2-ylmethoxy)-1-(phenylsulfonyl)-1H-indole;4-{[4-(azepan-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indole;4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indole;4-(azepan-2-ylmethoxy)-1-[(3-fluorophenyl)sulfonyl]-1H-indole;4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indazole;4-(azepan-2-ylmethoxy)-1-[(2-chlorophenyl)sulfonyl]-1H-indazole;4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indazole;1-(phenylsulfonyl)-5-(pyrrolidin-2-ylmethoxy)-1H-indazole;1-(phenylsulfonyl)-6-(pyrrolidin-2-ylmethoxy)-1H-indazole; thestereoisomers thereof; and the pharmaceutically acceptable saltsthereof.
 10. A method for the treatment of a disorder of the centralnervous system related to or affected by the 5-HT6 receptor in a patientin need thereof which comprises providing to said patient atherapeutically effective amount of a compound of formula I

wherein W is SO₂, CO, CONH, CSNH or (CH₂)_(x); X is O, SO_(y) or NR₁₃; Yis CR₁₄ or N; Z is CR₁₅ or N with the proviso that when Y is N then Zmust be CR₁₅; m and x are each independently 0 or an integer of 1, 2 or3; n and p are each independently an integer of 1, 2 or 3; R₁ ishalogen, CN, OR₁₆, CO₂R₁₇, CONR₁₈R₁₉, CNR₂₀NR₂₁R₂₂, SO₂NR₂₃R₂₄,SO_(w)R₂₅, or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, phenyl or heteroaryl group each optionallysubstituted; R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently H or an optionally substituted C₁-C₆alkyl group; R₄ is H,CNR₂₆NR₂₇R₂₈ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; R₁₂ is an optionally substituted C₁-C₆alkyl,aryl or heteroaryl group; y and w are each 0 or an integer of 1 or 2;R₁₃ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl aryl or heteroaryl group each optionally substituted;R₁₄ and R₁₅ are each independently H, halogen or a C₁-C₆alkyl, aryl,heteroaryl or C₁-C₆alkoxy group each optionally substituted; R₁₆ is H,COR₂₉ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, aryl or heteroarylgroup each optionally substituted; R₁₇ and R₂₉ are each independently Hor a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₆, R₂₇ and R₂₈ are each independently H or anoptionally substituted C₁-C₆alkyl group; R₂₃ and R₂₄ are eachindependently H or a C₁-C₆alkyl, aryl or heteroaryl group eachoptionally substituted; and R₂₅ is an optionally substituted C₁-C₆alkyl,aryl, or heteroaryl group; or the stereoisomers thereof or thepharmaceutically acceptable salts thereof.
 11. The method according toclaim 10 wherein said disorder is a motor disorder, anxiety disorder orcognitive disorder.
 12. The method according to claim 10 wherein saiddisorder is schizophrenia or depression.
 13. The method according toclaim 11 wherein said disorder is Alzheimer's disease or Parkinson'sdiease.
 14. The method according to claim 11 wherein said disorder isattention deficit disorder.
 15. A pharmaceutical composition whichcomprises a pharmaceutically acceptable carrier and an effective amountof a compound of formula I

wherein W is SO₂, CO, CONH, CSNH or (CH₂)_(x); X is O, SO_(y) or NR₁₃; Yis CR₁₄ or N; Z is CR₁₅ or N with the proviso that when Y is N then Zmust be CR₁₅; m and x are each independently 0 or an integer of 1, 2 or3; n and p are each independently an integer of 1, 2 or 3 with theproviso that when p is an integer of 1 then one of Y and Z must be N; R₁is halogen, CN, OR₁₆, CO₂R₁₇, CONR₁₈R₁₉, CNR₂₀NR₂₁R₂₂, SO₂NR₂₃R₂₄,SO_(w)R₂₅, or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, phenyl or heteroaryl group each optionallysubstituted; R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently H or an optionally substituted C₁-C₆alkyl group; R₄ is H,CNR₂₆NR₂₇R₂₈ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl; cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; R₁₂ is an optionally substituted C₁-C₆alkyl,aryl or heteroaryl group; y and w are each 0 or an integer of 1 or 2;R₁₃ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;R₁₄ and R₁₅ are each independently H, halogen or a C₁-C₆alkyl, aryl,heteroaryl or C₁-C₆alkoxy group each optionally substituted; R₁₆ is H,COR₂₉ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, aryl or heteroarylgroup each optionally substituted; R₁₇ and R₂₉ are each independently Hor a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₆, R₂₇ and R₂₈ are each independently H or anoptional substituted C₁-C₆alkyl group; R₂₃ and R₂₄ are eachindependently H or a C₁-C₆alkyl, aryl or heteroaryl group eachoptionally substituted; and R₂₅ is an optionally substituted C₁-C₆alkyl,aryl, or heteroaryl group; or the stereoisomers thereof or thepharmaceutically acceptable salts thereof.
 16. The composition accordingto claim 15 having a formula I compound wherein W is SO₂.
 17. Thecomposition according to claim 16 having a formula I wherein X is O. 18.The composition according to claim 16 having a formula I compoundwherein Y is CR₁₄ and n is
 1. 19. The composition according to claim 18having a formula I compound selected from the group consisting of:1-(phenylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;8-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)quinoline;1-[(2-chlorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;1-[(2-fluorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;1-[(5-chlorothien-2-yl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;4-({4-[(2S)-pyrrolidin-2-ylmethoxy}-1H-indazol-1-yl}sulfonyl)aniline;2-chloro-4-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)aniline;1-(phenylsulfonyl)-4-(piperidin-2-ylmethoxy)-1H-indole;4-{[4-(piperidin-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;1-[(3-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;1-[(2-chlorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;4-(azepan-2-ylmethoxy)-1-(phenylsulfonyl)-1H-indole;4-{[4-(azepan-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indole;4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indole;4-(azepan-2-ylmethoxy)-1-[(3-fluorophenyl)sulfonyl]-1H-indole;4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indazole;4-(azepan-2-ylmethoxy)-1-[(2-chlorophenyl)sulfonyl]-1H-indazole;4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indazole;1-(phenylsulfonyl)-5-(pyrrolidin-2-ylmethoxy)-1H-indazole;1-(phenylsulfonyl)-6-(pyrrolidin-2-ylmethoxy)-1H-indazole; thestereoisomers thereof; and the pharmaceutically acceptable saltsthereof.
 20. A process for the preparation of a compound of formula Ie

wherein X, Y, Z, m, n, p, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁and R₁₂ are defined in claim 1 which comprises reacting a compound offormula XVI

wherein X, Y, Z, m, n, p, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ andR₁₁ are as defined hereinabove with a sulfonyl chloride, R₁₂SO₂Cl,wherein R₁₂ is as defined hereinabove in the presence of a baseoptionally in the presence of a solvent.
 21. A compound of formula XVI

wherein X is O, SO_(y) or NR₁₃; Y is CR₁₄ or N; Z is CR₁₅ or N with theproviso that when Y is N then Z must be CR₁₅; m is 0 or an integer of 1,2 or 3; n and p are each independently an integer of 1, 2 or 3; R₁ ishalogen, CN, OR₁₆, CO₂R₁₇, CONR₁₈R₁₉, CNR₂₀NR₂₁R₂₂, SO₂NR23R₂₄,SO_(w)R₂₅, or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, phenyl or heteroaryl group each optionallysubstituted; R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently H or an optionally substituted C₁-C₆alkyl group; R₄ is H,CNR₂₆NR₂₇R₂₈ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl or cycloheteroalkyl group each optionally substituted;R₁₃ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl aryl or heteroaryl group each optionally substituted;R₁₄ and R₁₅ are each independently H, halogen or a C₁-C₆alkyl, aryl,heteroaryl or C₁-C₆alkoxy group each optionally substituted; R₁₆ is H,COR₂₉ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, aryl or heteroarylgroup each optionally substituted; R₁₇ and R₂₉ are each independently Hor a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₆, R₂₇ and R₂₈ are each independently H or anoptionally substituted C₁-C₆alkyl group; R₂₃ and R₂₄ are eachindependently H or a C₁-C₆alkyl, aryl or heteroaryl group eachoptionally substituted; and R₂₅ is an optionally substituted C₁-C₆alkyl,aryl, or heteroaryl group; or the stereoisomers thereof or thepharmaceutically acceptable salts thereof.
 22. The compound according toclaim 21 wherein X is O; Y is CR₁₄; and n is
 1. 23. The compoundaccording to claim 22 wherein Z is CR₁₅.